EP0173748A1 - Procede de preparation de composes non satures substitues contenant de cycles a six chainons a partir de derives de phenol - Google Patents

Procede de preparation de composes non satures substitues contenant de cycles a six chainons a partir de derives de phenol Download PDF

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EP0173748A1
EP0173748A1 EP85901054A EP85901054A EP0173748A1 EP 0173748 A1 EP0173748 A1 EP 0173748A1 EP 85901054 A EP85901054 A EP 85901054A EP 85901054 A EP85901054 A EP 85901054A EP 0173748 A1 EP0173748 A1 EP 0173748A1
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group
cyclodextrin
substituted
process according
reaction
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EP0173748B1 (fr
EP0173748A4 (fr
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Makoto Komiyama
Izuru Sugiura
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HIRAI Hidefumi
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HIRAI Hidefumi
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Priority claimed from JP59025589A external-priority patent/JPS60169438A/ja
Priority claimed from JP59073300A external-priority patent/JPS60215645A/ja
Priority claimed from JP59079067A external-priority patent/JPS60222438A/ja
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/008Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with tri- or tetrahalomethyl compounds
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/512Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being a free hydroxyl group
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/093Preparation of carboxylic acids or their salts, halides or anhydrides by hydrolysis of —CX3 groups, X being halogen

Definitions

  • This invention relates to a process for producing a para-substituted phenol derivative. More particularly, the present invention is concerned with a process for producing a para-substituted phenol derivative which comprises reacting a phenol compound with an organic halide selected from the group consisting of a haloform, a carbon tetrahalide and a substituted or unsubstituted allyl halide in the presence of an alkali metal hydroxide, using as a catalyst a fixed cyclodextrin having hydroxyl groups crosslinked with a bivalent hydrocarbon group having free valences at its both ends.
  • an organic halide selected from the group consisting of a haloform, a carbon tetrahalide and a substituted or unsubstituted allyl halide in the presence of an alkali metal hydroxide, using as a catalyst a fixed cyclodextrin having hydroxyl groups crosslinked with a bivalent hydrocarbon group having free val
  • 2,5-cyclohexadienone derivatives having a dihalomethyl group at the 4-position 2,5-cyclohexadienone derivatives having a substituted or unsubstituted allyl group at the 4-position, para-hydroxybenzoic acid derivatives, or para-hydroxybenzaldehyde derivatives are prepared by reacting a phenol with a haloform under alkaline conditions.
  • the products thus obtained are extremely valuable compounds as pharmaceuticals, agricultural chemicals, or raw materials for polymers, various physiologically active substances such as agricultural chemicals and pharmaceuticals, and dyes.
  • para-hydroxybenzaldehyde which, nowadays, is of increasing importance as an anticarcinogen or a raw material for pharmaceuticals, agricultural chemicals and dyes, has conventionally been synthesized by reacting phenol with chloroform in the presence of an alkali.
  • para-hydroxybenzaldehyde is obtained in a selectivity as low as about 30%, and a large amount of salicylaldehyde is formed as a by-product. Therefore, the production of para-hydroxybenzaldehyde in accordance with this process requires not only a large amount of raw materials but also a complicated operation for separation,
  • 2,4-Dihydroxybenzaldehyde nowadays, is also of increasing importance in view of its interesting behaviors such as cancer-controlling effect, plant root growth-promoting effect, antibacterial effect and photophosphorylation-controlling effect in chloroplast.
  • 2,4-dihydroxybenzaldehyde known is a process in which 1,3-dihydroxybenzene is reacted with chloroform in the presence of an alkali.
  • a large amount of 2,4-dihydroxy-3- formylbenzaldehyde is formed as a by-product, and 2,4-dihydroxybenzaldehyde which is the intended product is obtained only in low yield and with low selectivity. Accordingly, for producing 2,4-dihydroxybenzaldehyde by this process, not only large amounts of raw materials but also a complicated operation for separation is required.
  • the selectivity for the formation of para-hydroxybenzoic acid is 57 %, and the reaction gives a large amount of salicylic acid as a by-product. Therefore, the process also requires not only large amounts of raw materials but also a complicated operation for separation.
  • 2,5-Cyclohexadienone derivatives having an allyl group at the 4-position are also highly reactive due to the conjugation of two C-C double bonds and a carbonyl group, and therefore, are valuable as raw materials for the syntheses of physiologically active substances and other useful substances.
  • 2,5-cyclohexadienone derivatives themselves have physiological activities. Hitherto is known the Reimer-Tiemann reaction in which a para-substituted phenol is reacted with a haloform and sodium hydroxide or potassium hydroxide to give a 4-dihalomethyl-2,5-cyclohexadienone derivative.
  • the reaction however, gives as major product a compound having a substituent introduced mainly to the ortho-position. Therefore, the conventional process gives 2,5-cyclohexadienone derivatives in a yield as low as 5 to 10 %, and requires not only large amounts of raw materials but also a complicated operation for separation.
  • 2,5-Cyclohexadienone derivatives having an allyl group at the 4-position are also highly reactive due to the conjugation of two C-C double bonds and a carbonyl group. In addition, they have an allyl group at such a position that an intramolecular ring-forming reaction is readily caused to occur. Accordingly, the derivatives are valuable compounds as starting materials for preparing physiologically active substances and other useful substances.
  • 2,5-Cyclohexadienone derivatives having an allyl group at the 4-position have conventionally been prepared by a process comprising two steps, namely, the first step in which a 1:1 mixture of sodium methoxide and a para-substituted phenol is reacted with an allyl halide in an aromatic solvent to produce a 2,4-cyclohexadienone derivative which is allyl-substituted at the 6-position, and the second step in which the product in the first step is then reacted in a methanol-hydrochloric acid mixture to allow the allyl group to transfer to the 4-position.
  • the process however, has disadvantages that the 2,4-cyclohexadienone derivative which is a reaction product of the first step is difficult to separate and purify, and that the reactions involved in the process require large amounts of organic solvents.
  • cyclodextrin is soluble in an alkaline aqueous solution, and therefore, for recovering the cyclodextrin after completion of the reaction, it is required to acidify the reaction system by adding an acid thereto to deposite and separate the cyclodextrin therefrom.
  • Such an operation for recovering the cyclodextrin is not only troublesome but also has a disadvantage that 10 to 20 % of the cyclodextrin employed for the reaction is usually lost during the step of recovery. Accordingly, since cyclodextrin is highly expensive, the process is extremely disadvantageous in manufacturing the above-mentioned various valuable substances and intermediates thereof by reacting phenols with organic halides on a commercial scale.
  • hydroxychalcone and its derivatives nowaday, are of increasing importance as a remedy for gastrointestinal ulcers and tumors, as an anti-inflammatory agent, and as an intermediate for preparing a variety of pharmaceuticals, and agricultural chemicals.
  • 4-hydroxychalcone and its derivatives are prepared by reacting phenol with a haloform in the presence of an alkali to give 4-hydroxybenzaldehyde and reacting the obtained 4-hydroxybenzaldehyde with acetophenone or its derivative.
  • 4-hydroxy-3-carboxychalcone derivatives are prepared by reacting 4-hydroxybenzaldhyde with a carbon tetrahalide in the presence of an alkali to give 2-hydroxy-5-formylbenzoic acid and then reacting the obtained 2-hydroxy-5-formylbenzoic acid with acetophenone and its derivatives.
  • the above-mentioned processes are practiced, not only the intended products are obtained only in low yields but also large amounts of by-products are unfavorably produced. Therefore, the above-mentioned processes are impractical.
  • any of the conventional processes for preparing para-substituted phenol derivatives are unsatisfactory from a practical point of view because of extremely low selectivity, necessity of complicated steps for recovering the catalyst employed and much loss of catalyst.
  • the elimination of the disadvantages accompanying conventional processes has been strongly desired.
  • the present inventors have made extensive and intensive studies to develop a process for preparing para-substituted phenol derivatives, in which not only para-substituted phenol derivatives can be obtained in high yield and with high selectivity but also the catalyst is not lost and can be recovered easily from the reaction mixture.
  • the present inventors have surprisingly found that the disadvantages of the conventional processes can be eliminated by using as a catalyst a fixed cyclodextrin having hydroxyl groups crosslinked with a bivalent hydrocarbon group having free valences at its both ends and that the para-substituted phenol derivatives can be prepared extremely advantageously from a practical point of view.
  • the present inventors have found that, by employing the above-mentioned fixed cyclodextrin as a catalyst, the intended para-substituted phenol derivatives can be prepared in high yield and with high selectivity (of which the definition will be given later) and that since the fixed cyclodextrin is insoluble in the reaction system the employed fixed cyclodextrin can be recovered with great ease from the reaction mixture, for example, by centrifugation and filtration. Further, it has been surprisingly found that even when the recovered fixed cyclodextrin is repeatedly employed a* a catalyst the para-substituted phenol derivatives can be prepared without lowering in yield and selectivity. Based on such novel findings, the present invention has been made.
  • a process for producing a para-substituted phenol derivative which comprises reacting a phenol compound represented by the formula (I) wherein A, B, C, D and E each independently stand for hydrogen, a hydroxyl group, a carboxyl group, a sulfonic group, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted allyl group, a substituted or unsubstituted alkoxyl group or a substituted or unsubstituted aryl group, provided that A does not stand for a hydroxyl group, a carboxyl group and a sulfonic group and that when two or more of A, B, C, D, and E each independently stand for a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxyl gruoup, they have their respective free terminal ends or at least one of them is
  • an organic halide selected from the group consisting of a haloform, a carbon tetrahalide and a substituted or unsubstituted allyl halide in the presence of an alkali metal hydroxide, using as a catalyst a fixed cyclodextrin having hydroxyl groups crosslinked with a bivalent hydrocarbon group having free valences at its both ends, said hydrocarbon group having at least one hydrogen atom substituted or unsubstituted with a member selected from the group consisting of an alkyl group, a halogen atom and a hydroxyl group and containing or not containing at least one combination of two neighboring carbon atoms having therebetween at least one member selected from the group consisting of an oxygen atom, a sulfur atom and phenylene, thereby to obtain a reaction mixture containing a para-substituted phenol derivative; and (2) isolating the para-substituted phenol derivative from said reaction mixture.
  • an organic halide selected from
  • phenol compound as used herein is meant phenol (hydroxybenzene) or its derivative which is defined by the above-mentioned formula (1).
  • the substituted or unsubstituted alkyl group, the substituted or unsubstituted allyl group, the substituted or unsubstituted alkoxyl group and the substituted or unsubstituted aryl group each may preferably have carbon atoms of not more than 6 with respect to the substituents B, C, D and E, and each may preferably have carbon atoms of not more than 12 with respect to the substituent A.
  • the organic halide which is one of the reactants to be used in the process of the present invention is selected from the group consisting of a haloform, a carbon tetrahalide and a substituted or unsubstituted allyl halide.
  • the substituted or unsubstituted allyl halide may preferably have carbon atoms of not more than 12. As such an allyl halide, the chloride and bromide are especially preferred.
  • the organic halide may be used in an amount of 1 to 20 mols, preferably 1.5 to 10 mols per mol of the phenol compound used.
  • the alkali metal hydroxide to be used in the process of the present invention may preferably be sodium hydroxide or potassium hydroxide.
  • the alkali metal hydroxide may be used in a stoichiometrical amount relative to the phenol compound. Usually, however, 1 to 15 times, preferably 1.5 to 10 times the stoichiometrical amount of the alkali metal hydroxide may be used taking into consideration of the rate of reaction and the like.
  • the reaction according to the process of the present invention is usually carried out in a reaction medium.
  • a reaction medium there is employed an aqueous solvent, preferably water, because of the requirement that the reaction medium be capable of dissolving the alkali metal hydroxide therein.
  • an aqueous solvent preferably water
  • the reaction medium a mixture of water with a small amount of an organic solvent which is soluble in water and can be present stably under the reaction conditions.
  • an organic solvent include methanol, ethanol, acetone, dimethoxyethane and the like.
  • concentration of the alkali metal hydroxide in the reaction solvent may be in the range of 0.1 to 50 % by weight.
  • the preferred concentration of the alkali metal halide in the reaction medium varies depending on the kind of the organic halide to be employed. Specifically, where the organic halide is a haloform, the range of concentration is preferably 5 to 20 % by weight, more preferably 10 to 15 % by weight. Where the organic halide is a carbon tetrahalide or an allyl halide, the range of concentration is preferably 0.1 to 30 % by weight, more preferably 0.5 to 25 % by weight.
  • the concentration of the alkali metal hydroxide in the reaction medium is preferably 5 to 20 % by weight.
  • the fixed cyglgdextrin to be used in the process of the present invention is a granule solid or a gel, and the cyclodextrin has hydroxyl groups crosslinked with a bivalent hydrocarbon group having free valences at its both ends.
  • the fixed cyclodextrin is insoluble in the reaction system and remains unchanged chemically during the reaction.
  • the hydrocarbon group may have at least one hydrogen atom substituted with a member selected from the group consisting of an alkyl group, a halogen atom such as fluorine and chlorine, and a hydroxyl group. In this case, an alkyl group having 6 or less carbon atoms is preferred.
  • the hydrocarbon group may contain at least one combination of two neighboring carbon atoms having therebetween at least one member selected from the group consisting of an oxygen atom, a sulfur atom and a phenylene.
  • the number of oxygen atoms, sulfur atoms and phenylenes contained in the hydrocarbon group are preferably 8 or less, 8 or less and 2 or less, respectively.
  • the hydrocarbon group contains preferably 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms.
  • hydrocarbon group there may be mentioned groups represented by the following general formulae. But the hydrocarbon group is not limited to the groups represented by the following general formulae.
  • the preferable numbers of halogen atoms, hydroxyl groups and alkyl groups contained in the hydrocarbon group represented by the formulae given above are 20 or less, 10 or less and 4 or less, respectively.
  • hydrocarbon group there may be mentioned 2-hydroxypropylene, 2-hydroxybutylene, 2-hydroxypentylene, 2,9-dihydroxy-4,7-dioxadecylene, 2,10-dihydroxy-4,8-dioxaundecylene, and 2,11-dihydroxy-4,9-dioxadodecylene.
  • 2-hydroxypropylene and 2,9-dihydroxy-4,7-dioxadecylene are more preferred.
  • cyclodextrin to be crosslinked with the bivalent hydrocarbon group having free valences at its both ends there may be mentioned a modified or unmodified ⁇ -, ⁇ - or y-cyclodextrin.
  • a preferable kind of cyclodextrin varies according to the kind of the organic halide to be used.
  • the organic halide is a haloform
  • a-cyclodextrin and ⁇ -cyclodextrin are preferred, and ⁇ -cyclodextrin is more preferred.
  • the organic halide is a carbon tetrahalide
  • S-cyclodextrin is preferred.
  • the organic halide is an allyl halide
  • a-cyclodextrin and S-cyclodextrin are preferred, and a-cyclodextrin is more preferred.
  • a modified cyclodextrin When a modified cyclodextrin is used as the cyclodextrin, there may be employed a modified ⁇ -, ⁇ - or y-cyclodextrin of which the primary hydroxyl groups are all or partly substituted, for example, with a methoxy group.
  • a modified cyclodextrin When an allyl halide is used as the organic halide, a fixed modified a-cyclodextrin is particularly preferred.
  • the modified cyclodextrin may be prepared according to the method described in Helv. Chim. Acta, 61, 2190 (1978).
  • the fixed cyclodextrin in which a modified or unmodified cyclodextrin has hydroxyl groups crosslinked can be obtained by reacting the cyclodextrin with a crosslinking agent in the presence of an alkali metal hydroxide such as potassium hydroxide and sodium hydroxide.
  • a crosslinking agent there may be employed crosslinking agents represented by the formulae (IV'), (V'), (VI') and (VII') which respectively correspond to the hydrocarbon groups represented by the above-described formulae (IV), (V), (VI) and (VII).
  • epichlorohydrin epichlorohydrin, epibromohydrin and ethylene glycol diglycydyl ether are preferably employed as the crosslinking agent.
  • the molar ratio of the crosslinking agent to cyclodextrin in the reaction for crosslinking is preferably 1.0 to 30, and the molar ratio of the alkali metal hydroxide to the crosslinking agent is preferably in the range of 1.0 to 2.0.
  • the crosslinking reaction can be carried out in the presence of-both of an alkali metal hydroxide and sodium borohydride. In this case, the molar ratio of sodium borohydride to the crosslinking agent is preferably in the range of 0.001 to 0.1.
  • the reaction is generally effected at a temperature of 40° to 90°C.
  • the reaction time is not critical, but is generally 10 minutes to 4 hours.
  • the cyclodextrin content of the fixed cyclodextrin employed in the process of the present invention is preferably in the range of 20 to 96 % by weight, more preferably in the range of 40 to 96 %.
  • the cyclodextrin content of the fixed cyclodextrin can easily be adjusted by varying the kind of the crosslinking agent, the molar ratio of the crosslinking agent to cyclodextrin or the like.
  • the fixed cyclodextrin is granular solid, the cyclodextrin content may be determined by means of elementary analysis.
  • the fixed cyclodextrin is a gel, the cyclodextrin content may be determined by means of 1 H-NMR.
  • the molar ratio of the fixed cyclodextrin on the basis of cyclodextrin in the fixed cyclodextrin (hereinafter often referred to simply as "fixed cyclodextrin”) to the organic halide is preferably 0.001 to 20.
  • a more preferable range of the ratio of the fixed cyclodextrin to the organic halide varies depending on the kind of the organic halide to be used. Specifically, where the organic halide is a haloform, the molar ratio of the fixed cyclodextrin to the organic halide is preferably 0.5 to 10, more preferably 0.8 to 5.
  • the molar ratio of the fixed cyclodextrin to the carbon tetrahalide is preferably 0.001 to 5.
  • the organic halide is an allyl halide
  • the molar ratio of the fixed cyclodextrin to the allyl halide is preferably 0.01 to 10, more preferably 0.1 to 5.
  • all the amount of the organic halide to be used may be added to a solution containing a phenol compound, an alkali metal hydroxide and a fixed cyclodextrin at the time of initiation of the reaction.
  • the organic halide may be added to a system comprising a phenol compound, an alkali metal hydroxide and a fixed cyclodextrin so that the molar ratio of the fixed cyclodextrin to the organic halide is maintained at a value falling within the range as mentioned above.
  • the latter mode of process can be practiced by intermittently or gradually adding the organic halide to the above-mentioned system.
  • the para-substituted phenol derivatives can be obtained at a high selectivity even by the use of a small amount of the fixed cyclodextrin, leading to economical advantages.
  • the control of the molar ratio of the fixed cyclodextrin to the organic halide in the reaction system may be made by the following method.
  • part of the reaction mixture is taken, subjected to the determination of the organic halide contained therein by gas chromatography, and the rate of -addition of the organic halide to the reaction system is adjusted so that the molar ratio of the fixed cyclodextrin to the organic halide is maintained at a value falling within the range as mentioned above.
  • the fixed cyclodextrin may be used in an amount of 0.00001 to 10 in terms of molar ratio with respect to the phenol compound used.
  • a preferable molar ratio of the cyclodextrin to the phenol compound varies depending on the kind of the organic halide to be used. Specifically, where the organic halide is a haloform, the molar ratio of the fixed cyclodextrin to the phenol compound is preferably 0.00001 to 5, more preferably 0.01 to 5, particularly preferably 0.5 to 5.
  • the molar ratio of the cyclodextrin to the phenol compound is preferably 0.001 to 10, more preferably 0.001 to 1, particularly preferably 0,01 to 0.5.
  • the organic halide is an allyl halide
  • the molar ratio of the fixed cyclodextrin to the allyl halide is preferably 0.0001 to 10, more preferably 0.01 to 10, particularly preferably 0.1 to 5.
  • the reaction temperature is not critical, and may be suitably determined according to a phenol compound to be used, but generally is 0 to 120°C, preferably 20 to 100°C.
  • the reaction time is also not critical, and may be suitably determined according to the kinds of a phenol compound and an organic halide to be used, the amounts of reactants, reaction temperature, manner of addition of reactants and the like but generally is 10 minutes to 40 hours.
  • the reaction pressure is also not restricted, and the reaction is usually carried out at atmospheric pressure from a viewpoint of ease in operation.
  • a in the formula(I) is hydrogen
  • Y stands for an aldehyde group, a carboxyl group or a substituted or unsubstituted allyl group.
  • a in the formula(I) is a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted allyl group, a substituted or unsubstituted alkoxyl group or a substituted or unsubstituted aryl group
  • a para-substituted phenol derivative represented by the formula(III) wherein A, B, C, D and E are as defined above, provided that A does not stand for a hydroxyl group, a carboxyl group or a sufonic group, and
  • Z stands for a haloform residue or a substituted or unsubstituted allyl group.
  • a hydroxychalcone compound when said organic halide is a member selected from a haloform and a carbon tetrahalide, a hydroxychalcone compound can be obtained by,following the step(l) and before the step(2), (la) adding to said reaction mixture the following reactant system:
  • a reaction mixture containing an intended para-substituted phenol derivative is obtained by the above-mentioned reaction and, thereafter, the catalyst, i.e., the fixed cyclodextrin can easily be separated and recovered from the reaction mixture by methods such as centrifugation and filtration.
  • the recovered solid can be used again as a catalyst repeatedly.
  • the remaining reaction mixture from which the catalyst has been removed is subjected to extraction with ether.
  • the ether layer is washed with water and then dried to obtain a para-substituted phenol derivative.
  • the process of the present invention may be practiced by passing an alkaline aqueous solution containing a phenol compound and an organic halide over a fixed bed of a fixed cyclodextrin, or by contacting the solution with the fixed bed.
  • the process of the present invention may be practiced in such a manner that while passing an alkaline solution of a phenol over a fixed bed of a fixed cyclodextrin or contacting the solution with the bed, the phenol compound is reacted with a haloform and an acetophenone compound in this order, a haloform, a carbon tetrahalide and an acetophenone compound in this order, or a carbon tetrahalide, a haloform and an acetophenone in this order.
  • the reaction may be effected by adding a copper catalyst to the reaction system.
  • a copper catalyst there may be mentioned, for example, copper powders, copper(II) sulfate, a copper(II) halide and copper(II) oxide.
  • the copper catalyst is added in an amount of 1 to 10 % by weight based on the phenol compound.
  • the process of the present invention not only the intended para-substituted phenol derivatives can be produced in high yield and with high selectivity, but also the fixed cyclodextrin employed as the catalyst can extremely easily be separated and recovered from the reaction mixture by means of, for example, centrifugation and filtration without any loss of.the fixed cyclodextrin. Moreover, the recovered fixed cyclodextrin can be used repeatedly for the preparation of para-substituted phenol derivatives without lowering in yield and selectivity. Thus, the process of the present invention is extremely advantageous from the commercial standpoint.
  • Hydroxyl groups of ⁇ -cyclodextrin are crosslinked with 2-hydroxy-n-propylene group to prepare a solid, fixed 8-cyclodextrin in the manner as described below.
  • the resulting solid is washed with acetone 3 times and with water throughly, and then dried in vacuum at 60 °C for 12 hours.
  • a fixed S-cyclodextrin which is white particles having a particle diameter of 1-to 3 mm.
  • the carbon and hydrogen contents are found to be 47.0 % and 6.6 %, respectively. Therefore, the fixed ⁇ -cyclodextrin contains 87 % by weight of ⁇ -cyclodextrin.
  • the reaction is allowed to proceed at 80 °C for 15 hours under reflux by the use of a reflux condenser while agitating by means of a magnetic stirrer. After completion of the reaction, the catalyst is removed by decantation (recovery of catalyst: 100 %).
  • the obtained reaction mixture is acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 3 times. The ethyl ether layer is washed with water and then dried, thereby to obtain 2.1 g of a product.
  • the obtained product is subjected to analysis by liquid chromatography [using a column (LS410K, MeOH-100, 30 cm) manufactured and sold by Toyo Soda Co., Ltd., Japan at 20 °C, with a mixed solvent of water and ethanol (6:4)].
  • the product is a mixture of 2.0 g of para-hydroxybenzoic acid and 0.1 g of phenol and contains no salicylic acid. Namely, the yield of para-hydroxybenzoic acid is 91 % on molar basis, and the selectivity is 100 %.
  • the above-recovered catalyst and 1.5 g of phenol are added to 20 ml of an aqueous 20 % sodium solution.
  • To the resulting mixture are added 3 ml of carbon tetrachloride and 0.1 g of copper powder.
  • the reaction is allowed to proceed at 80 °C for 15 hours under reflux by the use of a reflux condenser while agitating by means of a magnetic stirrer.
  • the catalyst is removed by decantation (recovery of catalyst: 100 %).
  • the resulting solution is acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 3 times.
  • the ethyl ether layer is washed with water, and then dried, thereby to obtain 2.2 g of a product.
  • the obtained product is subjected to analysis by liquid chromatography.
  • the product is a mixture of 2.1 g of para-hydroxybenzoic acid and 0.1 g of phenol, and contains no salicylic acid. Namely, the yield of para-hydroxybenzoic acid is 95 % on molar basis and the selectivity is 100 %
  • Example 2 Substantially the same reagents and catalyst as in Example 1 are used, except that o-cresol (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) is used instead of phenol.
  • o-cresol special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan
  • the ether layer is washed with water, and then dried, thereby to obtain 1.9 g of a product.
  • the obtained product is subjected to analysis by liquid chromatography [using a column (LS410K, MeOH-100, 30cm) manufactured and sold by Toyo Soda Co., Ltd., Japan, at 25 °C, with a mixed solvent of water and ethanol (6:4)].
  • the product is a mixture of 1.8 g of 3-methyl-4-hydroxybenzoic acid and 0.1 g of o-cresol. Namely, the yield of 3-methyl-4-hydroxybenzoic acid is 85 % on molar basis, and the selectivity is 100 %.
  • Example 2 Sbustantially the same reagents and catalyst as in Example 1 are used,except that m-cresol (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) is used instead of phenol.
  • m-cresol special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan
  • Example 2 To 20 ml of an aqueous 20 % sodium hydroxide solution are added 1.5 g of the catalyst as prepared in Example 1 from S-cyclodextrin and epichlorohydrin and 1.5 g of m-cresol, and further are added 3 ml of carbon tetrachloride and 0.1 g of copper powder.
  • the reaction is allowed to proceed at 80 °C for 15 hours under reflux by the use of a reflux condenser while agitating by means of a magnetic stirrer. After completion of the reaction, the catalyst is removed by decantation (recovery of catalyst: 100 %).
  • the resulting solution is acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 3 times.
  • the ether layer is washed with water, and then dried, thereby to obtain 2.1 g of a product.
  • the obtained product is subjected to analysis by liquid chromatography [using a column (LS410K, MeOH-10, 30 cm) manufactured and sold by Toyo Soda Co., Ltd., Japan, at 25°C, with a mixed solvent of water and ethanol (6:4)].
  • the product is a mixture of 2.0 g of 2-methyl-4-hydroxybenzoic acid and 0.1 g of m-cresol. Namely, the yield of 2-methyl-4-hydroxybenzoic acid is 95 % on molar basis, and the selectivity is 100 %.
  • ⁇ -cyclodextrin 50 g of ⁇ -cyclodextrin is dissolved in 80 ml of an aqueous 50 % sodium hydroxide solution. To the resulting solution is added 50 mg of sodium borohydride. 68 ml of epichlorohydrin is dropwise added to the mixture with agitating by means of a magnetic stirrer. The resulting mixture is allowed to react at 50 °C for 40 minutes. The resulting solid is washed with acetone 3 times and with water thoroughly, and then dried in vacuum at 60 °C for 12 hours, thereby to obtain 52 g of a fixed B-cyclodextrin which is white particles having a particle diameter of 1 to 3 mm.
  • the elementary analysis of the fixed B-cyclodextrin shows that the carbon and hydrogen contents are 48.4 % and 7.1 %, respectively. Therefore, the fixed S-cyclodextrin contains 78 % by weight of ⁇ -cyclodextrin.
  • the obtained fixed ⁇ -cyclodextrin is used as a catalyst for the preparation of a para-substituted phenol derivative as described hereinafter.
  • the ether layer is washed with water, and then dried, thereby to obtain 1.9 g of a product.
  • the obtained product is subjected to analysis by liquid chromatography [using a column (LS 410K, MeOH-100,30 cm) manufactured and sold by Toyo Soda Co., Ltd., Japan, at 25 °C, with a mixed solvent of water and ethanol (6:4)] .
  • the product is a mixture of 1.8 g of para-hydroxybenzoic acid and 0.1 g of phenol. Namely, the yield of para-hydroxybenzoic acid is 82 % on molar basis, and the selectivity is 100 %.
  • Example 2 Substantially the same procedures as in Example 1 are. repeated for preparing para-hydroxybenzoic acid, except that 1.7 g of a-cyclodextrin is used instead of 1.5 g of the fixed ⁇ -cyclodextrin.
  • the resulting solution is acidified with 1 ml of 36 % hydrochloric acid, and subjected to filtration to separate B-cyclodextrin from the reaction solution.
  • the separated ⁇ -cyclodextrin is dried.
  • the filtrate is subjected to extrations each with 50 ml of ethyl ether 3 times.
  • the ethyl ether layer is washed with water, and then dried, thereby to obtain 2.1 g of a product.
  • the obtained product is subjected to analysis by liquid chromatography.
  • the product is a mixture of 2.0 g of para-hydroxybenzoic acid and 0.1 g of phenol, and contains no salicylic acid. Namely, the yield of para-hydroxybenzoic acid is 92 % on molar basis, and the selectivity is 100 %.
  • the filtrate is subjected to extractions each with 50 ml of ethyl ether 3 times.
  • the ethyl ether layer is washed with water, and then dried, thereby to obtain 2.0 g of a product.
  • the obtained product is subjected to analysis by liquid chromatography.
  • the product is a mixture of 1.9 g of para-hydroxybenzoic acid and 0.1 g of phenol and contains no salicylic acid. Namely, the yield of para-hydroxybenzoic acid is 90 % on molar basis, and the selectivity is 100 %.
  • chloroform is added dropwise so that the molar ratio of the fixed cyclodextrin to the chloroform in the reaction system is maintained at a level of 1.0 to 1.6.
  • the control of the molar ratio of the fixed cyclodextrin to chloroform in the reaction system is effected as follows.
  • the ether layer is washed with water, and then dried, thereby to obtain 0.58 g of a product.
  • the obtained product is subjected to analysis ..by means of Gas Chromatograph (Tenax GC column, 2 m, 300 °C).
  • Teenax GC column 2 m, 300 °C
  • the product is a mixture of 0.56 g of 4-hydroxybenzaldehyde and 0.02 g of phenol, and there is detected no 2-hydroxybenzaldehyde.
  • the yield of 4-hydroxybenzaldehyde is. 86 % on molar basis, and the selectivity is. 100 %.
  • Example 2 To 50 ml of an aqueous 20 % sodium hydroxide solution are added 4.50 g of the catalyst (fixed S-cyclodextrin) as prepared in Example 1 and 0.50 g of o-cresol. The resulting mixture is heated to 60 °C while agitating by means of a magnetic stirrer. Then, while dropwise adding 3 ml of chloroform (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) to the mixture in the same manner as in Example 5, the reaction is allowed to proceed for 12 hours. After completion of the reaction, the catalyst is removed by decantation. The recovery of the catalyst is 100 %.
  • chloroform special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan
  • the obtained reaction mixture is acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 3 times.
  • the ether layer is washed with water, and then dried, thereby to obtain 0.65 g of a product.
  • the analysis of the product by means of Gas Chromatograph shows that the product is a mixture of 0.61 g of 4-hydroxy-3-methylbenzaldehyde and 0.04 g of o-cresol. Namely, the yield of 4-hydroxy-3-methylbenzaldehyde is 87 % on molar basis, and the selectivity is 100 %.
  • Example 2 To 80 ml of an aqueous 10 % sodium hydroxide solution are added 2.0 g of the catalyst (fixed B-cyclodextrin) as prepared in Example 1 and 1.0 g (10.8 mmol) of phenol (first class grade reagent, manufactured and sold by Koso Chemical Co., Ltd., Japan). Then, while . dropwise adding to the mixture 1.5 ml (18.7 mmol) of chloroform (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) in the same manner as in Example 5, the reaction is allowed to proceed at 70 °C for 10 hours while agitating by means of a magnetic stirrer.
  • chloroform special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan
  • the reaction mixture is cooled thoroughly with ice, and 1.3 g (10.8 mmol) of acetophenone (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) is added little by little to the mixture.
  • the reaction is allowed to proceed at room temperature for 10 hours.
  • the catalyst is removed by decantation. The recovery of the catalyst is 100 %.
  • the resulting solution is acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ether 3 times. The ether layer is washed with water, and then dried, thereby to obtain 2.0 g of a product.
  • the obtained product is subjected to analysis by means of 701-type Gas Chromatograph manufactured by Ohkura Rikagaku Kenkyusho Co., Ltd., Japan (packing material: Uniport HP manufactured and sold by Gasukuro Kogyo inc., Japan; column length, 2 m; column temperature, 120 °C; carrier gas, helium).
  • packing material Uniport HP manufactured and sold by Gasukuro Kogyo inc., Japan; column length, 2 m; column temperature, 120 °C; carrier gas, helium.
  • the product is 4-hydroxychalcone entirely. Namely, the yield of the intended product is 84 % on molar basis, and the selectivity is 100 %.
  • the rate of addition of chloroform is controlled according to the method described in Example 5 so that the molar ratio of the fixed B-cyclodextrin (based on ⁇ -cyclodextrin) to the chloroform is maintained at a level of 1 to 2.
  • the reaction is allowed to proceed at 60 °C for 10 hours with agitating by means of a magnetic stirrer.
  • the reaction mixture is cooled thoroughly with ice, and 2.5 g (16.2 mmol) of 4-hydroxyacetophenone (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) is added little by little to the mixture.
  • the reaction is allowed to proceed at room temperature for 10 hours. Then, the catalyst is removed by decantation. The recovery of the catalyst is 100 %.
  • the resulting solution is acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 3 times. The ether layer is washed with water, and then dried, thereby to obtain 2.6 g of a product.
  • the product is subjected to determinations of infrared spectrum by means of IR-E type-spectrophotometer manufactured and sold by Japan Spectroscopic Co., Ltd., Japan, and l H-NMR spectrum by means of PS-100 type high resolution spectrometer manufactured and sold by Nihon Denshi Co., Ltd., Japan.
  • the infrared spectrum and 1 H-NMR spectrum of the product are in agreement with those of a standard sample of 2,4'-dihydroxy-5-carboxychalcone. Namely, the yield of the intended product is 86 % on molar basis and the selectivity is 100 %.
  • the resulting solution is acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 3 times.
  • the ether layer is washed with water, and then dried, thereby to obtain 2.8 g of a product.
  • the infrared spectrum and 1 H-NMR spectrum of the product are in agreement with those of a standard sample of 4,4'-dihydroxy-3-carboxychalcone. Namely, the yield of the intended product is 92 % on molar basis and the selectivity is 100 %.
  • the resulting solid is washed with acetone 3 times and with water thoroughly, and then dried in vacuum at 60 °C for 12 hours, thereby to obtain 46 g of a fixed a-cyclodextrin which is white particles having a particle diameter of 1 to 3 mm.
  • the elementary analysis of the fixed a-cyclodextrin shows that the carbon and hydrogen contents are 44.5 % and 6.3 %, respectively. Therefore, the fixed a-cyclodextrin contains 82 % by weight of a-cyclodextrin.
  • 4 -Hydroxybenzaldehyde is prepared in substantially the same manner as in Example 5 except that 4 .5 g of the above-obtained fixed a-cyclodextrin is used as a catalyst.
  • the recovery of the catalyst, the yield of and the selectivity for 4-hydroxybenzaldehyde are 100 %, 58 % on molar basis and 95 %, respectively.
  • 4-hydroxybenzaldehyde is prepared in substantially the same manner as in the above, except that the above-recovered catalyst is used.
  • the recovery of the catalyst, the yield of and the selectivity for 4-hydroxybenzaldehyde are 100 %, 65 % on molar basis and 95 %, respectively.
  • 4- H ydroxychalcone- is prepared in substantially the same manner as in Example 7,except that 4.5 g of the fixed a-cyclodextrin as prepared in Example 10 is used as a catalyst instead of the fixed a-cyclodextrin.
  • the recovery of the catalyst, the yield of and the selectivity for 4-hydroxychalcone are 100 %, 52 % on molar basis and 93 %, respectively.
  • the syntheses of 4-hydroxychalcone are carried out repeatedly using the above-recovered catalyst 5 times. As a result, the recovery of the catalyst is 100 %, and there is observed no lowering in activity and selectivity of the catalyst.
  • 2,4'-Dihydroxy-5-carboxychalcone is prepared in substantially the same manner as in Example 8,except that 4.5 g of the fixed a-cyclodextrin prepared in Example 10 is used as a catalyst instead of the fixed a-cyclodextrin.
  • the recovery of the catalyst, the yield of and the selectivity for 2,4-dihydroxy-5-carboxychalcone are 100 %, 53 % on molar basis and 93 %, respectively.
  • 4.4'-Dihydroxy-3-carboxychalcone is prepared in substantially the same manner as in Example 9, except that 4.5 g of the fixed a-cyclodextrin as prepared in Example 10 is used as a catalyst instead of the fixed S-cyclodextrin.
  • the recovery of the catalyst, the yield of and the selectivity for 4,4'-dihydroxy-3-carboxychalcone are 100 %, 51 % on molar basis and-92 %, respectively.
  • the rate of addition of allyl bromide is controlled according to the method described in Example 5 so that the molar ratio of the fixed a-cyclodextrin (based on a-cyclodextrin) to the allyl bromide is maintained at a level of 1 to 2.
  • the catalyst is removed by decantation. The recovery of the catalyst is 100 %.
  • the resulting solution is acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 5 times. The ether layer is dried, thereby to obtain 0.18 g of a product.
  • the analysis of the product by means of 1 H- NMR shows that the product contains 53 % of 2,4,6-trimethyl-4-allyl-2,5-cyclohexadienone and that the contents of 2,4,6-trimethyl-6-allyl-2,4-cyclohexadienone and 2,4,6-trimethylphenyl allyl ether are 26 % and 21 %, respectively. Namely, the yield of the intended product is 37 %, and the selectivity is 53 %.
  • a fixed modified cyclodextrin which is white particles having a particle diameter of 1 to 3 mm.
  • the elementary analysis of the fixed modified cyclodextrin shows that the carbon and hydrogen contents are 50.9 % and 7.7 %, respectively. Therefore, the fixed modified cyclodextrin contains 80 % by weight of the modified cyclodextrin.
  • 2,4,6-trimethyl-4-allyl-2,5-cyclohexadienone is prepared in substantially the same manner as in Example 14 except that 8.6 g of the fixed modified cyclodextrin as prepared above is used as a catalyst instead of the fixed a-cyclodextrin.
  • the recovery of the catalyst, the yield of and the selectivity for the intended product are 100 %, 48 % on molar basis and 78 %, respectively.
  • the catalyst is used repeatedly 5 times.
  • the recovery of the catalyst is 100 %, and there is observed no lowering in activity and selectivity of the catalyst.
  • the obtained product is subjected to analysis by liquid chromatography using a column (LS410 K, MeOH-100, 30 cm) manufactured and sold by Toyo Soda Co., Ltd., Japan, at 25 °C, with a mixed solvent of water and ethanol (6 : 4).
  • a mixed solvent of water and ethanol 6 : 4
  • the product is para-hydroxybenzoic acid. Namely, the yield of para-hydroxybenzoic acid is 95 % on molar basis and the selectivity is 100 %.
  • the produced solid is washed with acetone 3 times and with water thoroughly, and then dried in vacuum at 60 °C for 12 hours. There is obtained 44 g of a fixed 8-cyclodextrin which is white particles having a diameter of 1 to 3 mm.
  • the elementary analysis of the fixed B-cyclodextrin shows that the carbon and hydrogen contents are 52.8 % and 8.1 %, respectively. Therefore, the fixed S-cyclodextrin contains 60 % by weight of ⁇ -cyclodextrin.
  • the catalyst is removed by decantation (recovery of catalyst : 100
  • the resulting solution is acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 3 times.
  • the ether layer is washed with water, and then dried, thereby to obtain 2.0 g of a product.
  • the obtained product is subjected to analysis by liquid chromatography [using a column (LS410 K, MeOH-100, 30 cm) manufactured and sold by Toyo Soda Co., Ltd., at 25 °C, with a mixed solvent of water and ethanol (6 : 4)].
  • the product is a mixture of 1.9 g of para-hydroxybenzoic acid and 0.1 g of phenol and contains no salicylic acid. Namely, the yield of para-hydroxybenzoic acid is 86 % on molar basis and the selectivity is 100 % .
  • the above-recovered catalyst and 1.5 g of phenol were added to 20 ml of an aqueous 20 % sodium hydroxide solution.
  • To the resulting mixture are added 3 ml of carbon tetrachloride and 0.1 g of copper powder.
  • the reaction is allowed to proceed at 80 °C for 15 hours under reflux by the use of a reflux condenser while agitating by means of a magnetic stirrer.
  • the catalyst . is removed by decantation ( recovery of catalyst : 100 %).
  • the resulting solution is acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 3 times.
  • the ether layer is washed with water, and then dried, thereby to obtain 2.2 g of a product.
  • the product is subjected to analysis by liquid chromatography. As a result, it is found that the product is a mixture of 2.1 g of para-hydroxybenzoic acid and 0.1 g of phenol and contains no salicylic acid. Namely, the yield of and the selectivity for para-hydroxybenzoic acid are 95 % on molar basis and 100 %, respectively.
  • the catalyst is used repeatedly 5 times. As a result, there is observed no lowering in recovery, activity and selectivity of the catalyst.
  • the fixed cyclodextrin employed as the catalyst can extremely easily be recovered from the reaction mixture by means of, e.g., centrifugation and filtration without any loss of the fixed cyclodextrin.
  • the recovered fixed cyclodextrin can be used repeatedly as a catalyst in the process of the present invention without lowering in yield of and selectivity for para-substituted phenol derivatives, thus enabling the commercially advantageous production process of the desired products to be realized.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Divers dérivés utiles de phénol p-substitué peuvent être obtenus avantageusement en faisant réagir un composé de phénol avec un halogénure organique choisi dans le groupe formé par les haloformes, les tétrahalogénocarbones et les halogénures d'allyle substitués ou non substitués en présence d'un hydroxyde de métal alcalin, en utilisant comme catalyseur de la cyclodextrine immobilisée réticulée par ses groupes hydroxy avec un groupe hydrocarbyle bivalent possédant des valences libres aux deux extrémités, substitué facultativement par un substituant choisi parmi un groupe alcoyle, un atome d'halogène et un groupe hydroxy, et possédant facultativement au moins un élément choisi dans le groupe formé par un atome d'oxygène, un atome de soufre et un phénylène entre au moins une partie des atomes de carbone voisins. Le catalyseur de cyclodextrine utilisé peut être récupéré facilement et sans perte; il peut être utilisé de manière répétitive pour ce procédé sans réduire le rendement et la sélectivité du dérivé de phénol.
EP85901054A 1984-02-14 1985-02-13 Procede de preparation de composes non satures substitues contenant de cycles a six chainons a partir de derives de phenol Expired - Lifetime EP0173748B1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP25589/84 1984-02-14
JP59025589A JPS60169438A (ja) 1984-02-14 1984-02-14 パラヒドロキシ安息香酸類の合成方法
JP73300/84 1984-04-12
JP59073300A JPS60215645A (ja) 1984-04-12 1984-04-12 パラヒドロキシベンズアルデヒド類の合成方法
JP59079067A JPS60222438A (ja) 1984-04-19 1984-04-19 ヒドロキシカルコン類の合成方法
JP79067/84 1984-04-19

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Cited By (1)

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EP0539243A2 (fr) * 1991-10-25 1993-04-28 Hidefumi Hirai Procédé pour l'introduction d'un groupe carboxylique dans l'acide carboxylique aromatique ou son dérivé

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PL377712A1 (pl) 2003-02-13 2006-02-06 Wellstat Therapeutics Corporation Związki do leczenia zaburzeń metabolicznych
US7915429B2 (en) 2006-01-25 2011-03-29 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US7820721B2 (en) 2006-01-25 2010-10-26 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
NZ570334A (en) 2006-02-02 2011-07-29 Wellstat Therapeutics Corp Compounds for the treatment of metabolic disorders
CN104725207B (zh) * 2014-01-11 2016-08-17 天长市天佳化工科技有限公司 一种4-甲基-4-三氯甲基-2,5-环己二烯-1-酮的制备方法
KR20210136990A (ko) 2019-03-06 2021-11-17 혼슈우 카가쿠고교 가부시키가이샤 4-히드록시-2-메틸안식향산의 제조방법

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WO1982003073A1 (fr) * 1981-03-09 1982-09-16 Hirai Hidefumi Procede permettant d'introduire un substituant dans une position p d'un phenol
JPS58170729A (ja) * 1982-03-31 1983-10-07 Hidefumi Hirai ヒドロキシカルコン類の合成法
JPS58194835A (ja) * 1982-05-07 1983-11-12 Hidefumi Hirai 4−アリル−2,5−シクロヘキサジエノン誘導体の合成方法

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WO1982003073A1 (fr) * 1981-03-09 1982-09-16 Hirai Hidefumi Procede permettant d'introduire un substituant dans une position p d'un phenol
JPS58170729A (ja) * 1982-03-31 1983-10-07 Hidefumi Hirai ヒドロキシカルコン類の合成法
JPS58194835A (ja) * 1982-05-07 1983-11-12 Hidefumi Hirai 4−アリル−2,5−シクロヘキサジエノン誘導体の合成方法

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0539243A2 (fr) * 1991-10-25 1993-04-28 Hidefumi Hirai Procédé pour l'introduction d'un groupe carboxylique dans l'acide carboxylique aromatique ou son dérivé
EP0539243A3 (en) * 1991-10-25 1993-05-19 Hidefumi Hirai Process for introducing a carboxyl group to an aromatic carboxylic acid or a derivative thereof
US5319134A (en) * 1991-10-25 1994-06-07 Hidefumi Hirai Process for introducing a carboxyl group to an aromatic carboxylic acid or a derivative thereof

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EP0173748B1 (fr) 1990-01-03
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AU576457B2 (en) 1988-08-25
DE3575127D1 (de) 1990-02-08
AU3938585A (en) 1985-09-10
EP0173748A4 (fr) 1986-07-23

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